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Can you really be allergic to an “inactive” ingredient?

Published online: December 14, 2018

Macrogols, including polyethylene glycols (PEGs) and the structurally related polysorbates, are compounds whose primary feature includes polyether groups. They have wide ranging use in medical and commercial settings, with molecular weights (MW) that range from 200 to 35,000 grams/mol. PEGs of MW between 3350 and 6000 are frequently used as inactive ingredients in many liquid and solid formulations of medications. PEGs of MW 3350 are also the primary ingredient in commonly used oral bowel preparations for colonoscopy procedures in the United States. Recently, PEGs of this MW range have been receiving attention as a cause of severe immediate allergic reactions to bowel preparations used for colonoscopies, and as a cause of reactions to chemotherapy drugs which have been conjugated to PEGs. Currently, there is only limited awareness of the role of PEGs in reactions to medications where they are present as an ingredient. The degree to which PEG hypersensitivity might be a problem in the United States and the mechanism for PEG and polysorbate reactions are therefore not well understood. After two cases of life-threatening immediate hypersensitivity to macrogols were encountered in their clinic, Stone, et al sought to further understand the mechanism and scope of immediate hypersensitivity to PEGs in the United States.

In an article published in The Journal of Allergy and Clinical Immunology: In Practice, the authors first obtained detailed clinical case descriptions from two patients whose history suggested an immediate reaction to PEG 3350-containing colonoscopy preparations, laxatives, or injected corticosteroids. They then determined these patients’ clinical reactivity to macrogols, including polyethylene glycols and polysorbate-containing products, using a combination of controlled skin prick, intradermal and challenge tests. To better understand the mechanism of macrogol hypersensitivity in the two cases, they next sought to detect the presence of polyethylene glycol specific antibodies using modified ELISA techniques.  They compared antibody concentrations to PEG 3350-exposed controls who had never reacted to it.  Finally, they evaluated the scope to which polyethylene glycol 3350 might be associated with anaphylaxis in the United States, by reviewing publicly available FDA Adverse Event Reporting System (FAERS) data and identified medications which contained either  PEG 3350 or  polysorbate 80 in the publicly available NIH Daily Med database.

Each of the cases had positive skin testing and reproducible symptoms to products containing either polyethylene glycol 3350, polysorbate 80, or both. Compared to controls who had been exposed to polyethylene glycol 3350-containing bowel preparations without allergic reactions, both of the cases had significantly increased amounts of specific IgG and IgE antibodies which could bind specifically to polyethylene glycols.  The binding of these antibodies increased as the molecular weight of the polyethylene glycol increased, suggesting that higher molecular weight PEG products like PEG 3350 might be more likely to cause a reaction.  The authors found an average of 4 cases of anaphylaxis reported per year to the FDA from 2005-2017 where PEG 3350-containing bowel preparations or laxatives were the implicated culprit.  PEG 3350 is currently contained in 1155 FDA approved medications and can more commonly be found in film coated tablets, topical gels, and parenteral steroids. Polysorbate 80 is currently contained in 6821 FDA approved medications and can more commonly be found in film coated tablets, parenteral steroids, immunoglobulin replacement, and vaccines.

High molecular weight polyethylene glycols and polysorbates are common ingredients in a wide variety of medications, household products and industrial products which may provide a vehicle for sensitizing susceptible individuals.  Allergists and consumers should be aware that sensitization leading to an immediate hypersensitivity type allergy to polyether containing compounds such as polyethylene glycols and polysorbates can occur, and that such reactions may currently be under-recognized.  It remains to be determined the degree to which sensitized patients can react to medications which contain only tiny amounts of PEGs or polysorbates, compared to the much larger amounts contained in certain injectable drugs, oral colonoscopy preparations, and laxatives.

The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.